GRIK2 & Bipolar Disorder

Ashley Bateman

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Bipolar Disorder (BPD)Manic-depressive disorder

Extreme and unusual shifts in mood, energy, and ability to function

Damages relationships & performance

Often ends in suicide

Affects > 5 million Americans, 3 in 100 adults

Diagnosis

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http://beingbipolar.today.com/files/2009/04/history-of-bipolar-disorder.jpg

Major Depressive Episode

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Persistent feelings of:

Sadness

Anxiety

Guilt

Anger

Isolation

Hopelessness

Disturbances in sleep and appetite

Fatigue and loss of interest in sexual activity

Irritability

Lack of motivation

Morbid suicidal ideation

Manic Episode

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Distinct period of:

Elevated, expansive, irritable mood state

Racing thoughts

Low attention span

Easily distracted

Impaired judgment

Spending sprees, unusual behavior

Substance abuse (esp. alcohol, stimulants)

Aggressive behavior

Increased sexual drive

Famous People with BPD

Hollywood:Britney SpearsJim CareyRobert Downey Jr.Linda HamiltonVivien LeighBen StillerRobin WilliamsRichard DreyfussMarilyn MonroeTim BurtonFrancis Ford Coppola

Musicians:

Beethoven

Mozart

DMX

Jimi Hendrix

Axl Rose

Sting

Brian Wilson

Kurt Cobain

Ozzy Ozbourne

Politicians:

Winston Churchill

Theodore Roosevelt

Abraham Lincoln

Napoleon Bonaparte

Writers:

Edgar Allen Poe

Mark Twain

Virginia Woolf

Charles Dickens

Ralph Waldo Emerson

F. Scott Fitzgerald

Ernest Hemingway

Kurt Vonnegut

Emily Dickinson

T.S. Eliot

Hans Christian Anderson

Victor Hugo

Scientists:Sir Isaac NewtonFlorence Nightingale

Sigmund FreudPlato

Charles Darwin!

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Genetic Cause of BPD?Many chromosomal regions and candidate genes appear to relate to the development of BPD

Inconsistent results and scattered focus, results not replicated

Epigenetics & environment?

Heritability = 0.71

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Part 1

Understand Gene & Protein

GRIK2 (humans)

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Neurological Correlates: The Neuroscience of Dysfunctional Behavior. Image retrieved on February 3rd, 2009. http://neurologicalcorrelates.com/wordpress/

Localized on chromosome 6

Glutamate, Receptor, Ionotropic, Kainate 2

Glutamate ligand

Excitatory and inhibitor neurotransmission

GluR6 subunit mutation impairs binding site

Arrows indicate gluR6 mutation sites

Isoforms

2nd variant: additional exon at the 3’ endFrameshift & early translation terminationShorter with distinct C-terminus

GRIK2 gene: 678026 bpGRIK2 coding mRNA: 4550 bp

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Gene function: Ontology

GO Consortium

Biological processCellular component &

molecular function

Glutamate signaling pathway, kainate selective glutamate receptor activity

Neuronal transmission events: synaptic transmission and plasticity

Cell death & apoptosishttp://www.nature.com/nrn/journal/v9/n6/images/nrn2379-f1.jpg

GRIK2 Homologs

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GRIK2 homologues: Phylogeny

Multiple alignment using Muscle & Tcoffee

Phylogeny created using Phylogeny.fr

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Protein Motifs

PFAM/SMART

Identical result for every species’ sequence query

Highly conserved nature of putative functional domains

Localization in the Cell

Based on what we know about receptor function, should be localized to the plasma membrane

ESLpred: nucleus ???

TargetP: secretory pathway signal peptide (SP)

LOCATE: secreted protein? & type I membrane protein & multipass membrane protein

pTARGET: 100% confidence = plasma membrane

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Protein Networks

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Key Protein PlayersPSD95GRIP1PICK1SDCBPKLHL17KIF17GRIK4PRKAA1FOSSENP1

Interacts at postsynaptic sites, form scaffold

Glutamate Receptor Interacting Protein: localized scaffold, mediation of trafficking of binding partners

Protein Interacting w/ Protein Kinase C: adaptor that organizes subcellular location of membrane proteins

Scaffold Protein Periplasmic Binding Protein: binds the C-terminal domains of transmembrane proteins

May play a role in neuronal function

Kinesin Family Member: transports NMDA vesiclesGlutamate Receptor, Ionotropic, Kainate 4:

excitatory neurotransmitter at synapses in CNSProtein Kinase, AMP-activated, Alpha1 subunit:

cellular energy sensor conserved in all eukaryotic cells

Switch Regulatory Protein, associated with apoptotic cell death

Sentrin/SUMO-specific protease: covalent modification of proteins by the small ubiquitin-like protein SUMO

Part 2

Phenotypic Studies

Primary Literature

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Very few studies done on phenotype of GRIK2 mutant, other putative genes for BPD

Rationale

Recent human genetic studies:GRIK2 as potential BPD susceptibility geneGenetic linkage of BPD to

chromosome 6Genome-wide significant linkage est. by meta-analysisSpecific haplotype associated with BPDPost-mortem studies

Expression of kainate receptors in areas for mood regulation

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Study Questions

1. Used GluR6 KO mice in behavioral tests to elucidate role of GRIK2 receptor in regards to phenotypic patterns of BPD

2. Determine potential specificity of this receptor (receptor control = GluR5)

3. Effects of lithium on GluR6 KO mice4. Biochemical tests

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Behavioral Tests

Passive-avoidance testOpen-field testMonitoring home cage activitySocial interaction testElevated plus-maze testForced swim testResident intruder test

Same tests done with amphetamine & lithium

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Lithium Results

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Specific biochemical mechanism of action in mania unknown

Reduced spontaneous locomotor activity

Decreased aggressive behavior

Decreased activity in anxiety-provoking regions

Effect on elevated plus maze test

Reduced immobility time in forced swim test

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11125&loc=ec_rcshttp://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=401

Amphetamine Results

GluR6 KO mice:exhibited more spontaneous activitymore responsive to amphetaminemore aggressiveless anxious/more risk-taking behaviorless immobility in forced swim test

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Future Directions

Mice mutant KO of other putative BPD genes

RNAi difficult because of neuronal tissue

TAP tags for protein complexes of GRIK2

More (repeated) genetic linkage and mapping studies of bipolar families

Role of lithium

MORE RESEARCH!MORE RESEARCH!